In most cases, macroautophagy/autophagy serves to alleviate cellular stress and acts in a pro-survival manner. However, the effects of autophagy are highly contextual, and autophagic cell death (ACD) is emerging as an alternative paradigm of (stress- and drug-induced) cell demise. AT 101 ([-]-gossypol), a natural compound from cotton seeds, induces ACD in glioma cells as confirmed here by CRISPR/Cas9 knockout of ATG5 that partially, but significantly rescued cell survival following AT 101 treatment. Global proteomic analysis of AT 101-treated U87MG and U343 glioma cells revealed a robust decrease in mitochondrial protein clusters, whereas HMOX1 (heme oxygenase 1) was strongly upregulated. AT 101 rapidly triggered mitochondrial membrane depolarization, engulfment of mitochondria within autophagosomes and a significant reduction of mitochondrial mass and proteins that did not depend on the presence of BAX and BAK1. Conversely, AT 101-induced reduction of mitochondrial mass could be reversed by inhibiting autophagy with wortmannin, bafilomycin A1 and chloroquine. Silencing of HMOX1 and the mitophagy receptors BNIP3 (BCL2 interacting protein 3) and BNIP3L (BCL2 interacting protein 3 like) significantly attenuated AT 101-dependent mitophagy and cell death. Collectively, these data suggest that early mitochondrial dysfunction and HMOX1 overactivation synergize to trigger lethal mitophagy, which contributes to the cell killing effects of AT 101 in glioma cells.
Apolipoprotein A-IV is a member of the apo A-I/C-III/A-IV gene cluster. In order to investigate its hypothetical coordinated regulation, an acute phase was induced in pigs by turpentine oil injection. The hepatic expression of the gene cluster as well as the plasma levels of apolipoproteins were monitored at different time periods. Furthermore, the involvement of the inflammatory mediators' interleukins 1 and 6 and tumor necrosis factor in the regulation of this gene cluster was tested in cultured pig hepatocytes, incubated with those mediators and apo A-I/C-III/A-IV gene cluster expression at the mRNA level was measured. In response to turpentine oil-induced inflammation, a decreased hepatic apo A-IV mRNA expression was observed (independent of apo A-I and apo C-III mRNA) not correlating with the plasma protein levels. The distribution of plasma apo A-IV experienced a shift from HDL to larger particles. In contrast, the changes in apo A-I and apo C-III mRNA were reflected in their corresponding plasma levels. Addition of cytokines to cultured pig hepatocytes also decreased apo A-IV and apo A-I mRNA levels. All these results show that the down-regulation of apolipoprotein A-I and A-IV messages in the liver may be mediated by interleukin 6 and TNF-alpha. The well-known HDL decrease found in many different acute-phase responses also appears in the pig due to the decreased expression of apolipoprotein A-I and the enlargement of the apolipoprotein A-IV-containing HDL. 相似文献
Synopsis Iceland is unique in terms of geologically young freshwater systems and rapid adaptations of fresh water fishes to diverse
habitats, e.g. lava with ground water flow. Iceland has six species of freshwater fishes, including Arctic charr, Salvelinus alpinus. Previous research has shown great diversity within this species. Four different morphs of Arctic charr are found in one
lake, Thingvallavatn, including a small benthivorous charr. Similar populations of small benthic charr are known from several
other Icelandic freshwater locations, including Nautavakir in Grímsnes. Our comparison of the small benthic charr morphs in
Thingvallavatn and in Grímsnes showed that they are similar in morphology but distinguishable in several characteristics.
Small benthic charr in Grímsnes and Thingvallavatn demonstrate similar adaptations and are an example of parallel evolution.
However, subtle morphological differences between them indicate further specialized adaptations at each location. 相似文献
In popular use of Bayesian phylogenetics, a default branch-length prior is almost universally applied without knowing how a different prior would have affected the outcome. We performed Bayesian and maximum likelihood (ML) inference of phylogeny based on empirical nucleotide sequence data from a family of lichenized ascomycetes, the Psoraceae, the morphological delimitation of which has been controversial. We specifically assessed the influence of the combination of Bayesian branch-length prior and likelihood model on the properties of the Markov chain Monte Carlo tree sample, including node support, branch lengths, and taxon stability. Data included two regions of the mitochondrial ribosomal RNA gene, the internal transcribed spacer region of the nuclear ribosomal RNA gene, and the protein-coding largest subunit of RNA polymerase II. Data partitioning was performed using Bayes' factors, whereas the best-fitting model of each partition was selected using the Bayesian information criterion (BIC). Given the data and model, short Bayesian branch-length priors generate higher numbers of strongly supported nodes as well as short and topologically similar trees sampled from parts of tree space that are largely unexplored by the ML bootstrap. Long branch-length priors generate fewer strongly supported nodes and longer and more dissimilar trees that are sampled mostly from inside the range of tree space sampled by the ML bootstrap. Priors near the ML distribution of branch lengths generate the best marginal likelihood and the highest frequency of "rogue" (unstable) taxa. The branch-length prior was shown to interact with the likelihood model. Trees inferred under complex partitioned models are more affected by the stretching effect of the branch-length prior. Fewer nodes are strongly supported under a complex model given the same branch-length prior. Irrespective of model, internal branches make up a larger proportion of total tree length under the shortest branch-length priors compared with longer priors. Relative effects on branch lengths caused by the branch-length prior can be problematic to downstream phylogenetic comparative methods making use of the branch lengths. Furthermore, given the same branch-length prior, trees are on average more dissimilar under a simple unpartitioned model compared with a more complex partitioned models. The distribution of ML branch lengths was shown to better fit a gamma or Pareto distribution than an exponential one. Model adequacy tests indicate that the best-fitting model selected by the BIC is insufficient for describing data patterns in 5 of 8 partitions. More general substitution models are required to explain the data in three of these partitions, one of which also requires nonstationarity. The two mitochondrial ribosomal RNA gene partitions need heterotachous models. We found no significant correlations between, on the one hand, the amount of ambiguous data or the smallest branch-length distance to another taxon and, on the other hand, the topological stability of individual taxa. Integrating over several exponentially distributed means under the best-fitting model, node support for the family Psoraceae, including Psora, Protoblastenia, and the Micarea sylvicola group, is approximately 0.96. Support for the genus Psora is distinctly lower, but we found no evidence to contradict the current classification. 相似文献
Direct cellular contact with stimulated T cells is a potent mechanism that induces cytokine production in human monocytes in the absence of an infectious agent. This mechanism is likely to be relevant to T cell-mediated inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. Microparticles (MP) generated by stimulated T cells (MPT) display similar monocyte activating ability to whole T cells, isolated T cell membranes, or solubilized T cell membranes. We previously demonstrated that high-density lipoproteins (HDL) inhibited T cell contact- and MPT-induced production of IL-1β but not of its natural inhibitor, the secreted form of IL-1 receptor antagonist (sIL-1Ra).
Methodology/Principal Findings
Labeled MPT were used to assess their interaction with monocytes and T lymphocytes by flow cytometry. Similarly, interactions of labeled HDL with monocytes and MPT were assessed by flow cytometry. In parallel, the MPT-induction of IL-1β and sIL-1Ra production in human monocytes and the effect of HDL were assessed in cell cultures. The results show that MPT, but not MP generated by activated endothelial cells, bond monocytes to trigger cytokine production. MPT did not bind T cells. The inhibition of IL-1β production by HDL correlated with the inhibition of MPT binding to monocytes. HDL interacted with MPT rather than with monocytes suggesting that they bound the activating factor(s) of T cell surface. Furthermore, prototypical pro-inflammatory cytokines and chemokines such as TNF, IL-6, IL-8, CCL3 and CCL4 displayed a pattern of production induced by MPT and inhibition by HDL similar to IL-1β, whereas the production of CCL2, like that of sIL-1Ra, was not inhibited by HDL.
Conclusions/Significance
HDL inhibit both MPT binding to monocytes and the MPT-induced production of some but not all cytokines, shedding new light on the mechanism by which HDL display their anti-inflammatory functions. 相似文献
Suicide claims over one million lives worldwide each year. In the United States, 1 per 10,000 persons dies from suicide every year, and these rates have remained relatively constant over the last 20 years. There are nearly 25 suicide attempts for each suicide, and previous self-directed violence is a strong predictor of death from suicide. While many studies have focused on suicides, the epidemiology of non-fatal self-directed violence is not well-defined.
Objective
We used a nationally representative survey to examine demographics and underlying psychiatric disorders in United States (US) hospitalizations with non-fatal self-directed violence (SDV).
Method
International Classification of Disease, 9th Revision (ICD-9) discharge diagnosis data from the National Hospital Discharge Survey (NHDS) were examined from 1997 to 2006 using frequency measures and adjusted logistic regression.
Results
The rate of discharges with SDV remained relatively stable over the study time period with 4.5 to 5.7 hospitalizations per 10,000 persons per year. Excess SDV was documented for females, adolescents, whites, and those from the Midwest or West. While females had a higher likelihood of self-poisoning, both genders had comparable proportions of hospitalizations with SDV resulting in injury. Over 86% of the records listing SDV also included psychiatric disorders, with the most frequent being affective (57.8%) and substance abuse (37.1%) disorders. The association between psychiatric disorders and self-injury was strongest for personality disorders for both males (OR = 2.1; 95% CI = 1.3–3.4) and females (OR = 3.8; 95% CI = 2.7–5.3).
Conclusion
The NHDS provides new insights into the demographics and psychiatric morbidity of those hospitalized with SDV. Classification of SDV as self-injury or self-poisoning provides an additional parameter useful to epidemiologic studies. 相似文献
The link between the deregulation of autophagy and cell death processes can be essential in the development of several neurodegenerative diseases, such as Parkinson disease (PD). However, the molecular mechanism of deregulation of this degradative process in PD patients is unknown. The leucine-rich repeat kinase 2 (LRRK2) gene is related to PD and its implication in autophagy regulation has been described. Our recent work shows that the presence of the G2019S LRRK2 mutation, one of the most prevalent in LRRK2, is accompanied by a deregulation of autophagy basal levels dependent on the MAPK1/3 (ERK2/1) pathway. 相似文献